Abstract
ObjectivesIncreased plasma C-reactive protein (CRP) levels are associated with the occurrence and severity of acute coronary syndrome. We investigated whether CRP can be generated in vascular endothelial cells (ECs) after exposure to the most electronegative subfraction of low-density lipoprotein (LDL), L5, which is atherogenic to ECs. Because L5 and CRP are both ligands for the lectin-like oxidized LDL receptor-1 (LOX-1), we also examined the role of LOX-1.Methods and ResultsPlasma LDL samples isolated from asymptomatic hypercholesterolemic (LDL cholesterol [LDL-C] levels, 154.6±20 mg/dL; n = 7) patients and normocholesterolemic (LDL-C levels, 86.1±21 mg/dL; P<0.001; n = 7) control individuals were chromatographically resolved into 5 subfractions, L1-L5. The L5 percentage (L5%) and the plasma L5 concentration ([L5] = L5% × LDL-C) in the patient and control groups were 8.1±2% vs. 2.3±1% (P<0.001) and 12.6±4 mg/dL vs. 1.9±1 mg/dL (P<0.001), respectively. In hypercholesterolemic patients treated with atorvastatin for 6 months (10 mg/day), [L5] decreased from 12.6±4 mg/dL to 4.5±1.1 mg/dL (P = 0.011; n = 5), whereas both [L5] and L5% returned to baseline levels in 2 noncompliant patients 3 months after discontinuation. In cultured human aortic ECs (HAECs), L5 upregulated CRP expression in a dose- and time-dependent manner up to 2.5-fold (P<0.01), whereas the least electronegative subfraction, L1, had no effect. DiI-labeled L1, internalized through the LDL receptor, became visible inside HAECs within 30 seconds. In contrast, DiI-labeled L5, internalized through LOX-1, became apparent after 5 minutes. L5-induced CRP expression manifested at 30 minutes and was attenuated by neutralizing LOX-1. After 30 minutes, L5 but not L1 induced reactive oxygen species (ROS) production. Both L5-induced ROS and CRP production were attenuated by ROS inhibitor N-acetyl cysteine.ConclusionsOur results suggest that CRP, L5, and LOX-1 form a cyclic mechanism in atherogenesis and that reducing plasma L5 levels with atorvastatin disrupts the vascular toxicity of L5.
Highlights
Atherosclerosis is an inflammatory disease caused by the deposit of lipids within the vessel wall, which can be induced by multiple factors including age, smoking, endothelial dysfunction, and reactive oxygen species (ROS) [1]
Our results suggest that C-reactive protein (CRP), L5, and LDL receptor-1 (LOX-1) form a cyclic mechanism in atherogenesis and that reducing plasma L5 levels with atorvastatin disrupts the vascular toxicity of L5
After 6 months of statin treatment, the L5 percentage in hypercholesterolemic patients was significantly reduced to 4.560.8% (P = 0.022; Table 2), and the total low-density lipoprotein (LDL) cholesterol (LDL-C) concentration was reduced from 154.6620 mg/dL at baseline to 100612 mg/dL (Table 2)
Summary
Atherosclerosis is an inflammatory disease caused by the deposit of lipids within the vessel wall, which can be induced by multiple factors including age, smoking, endothelial dysfunction, and reactive oxygen species (ROS) [1]. In addition to being an acute-phase inflammatory marker, CRP is considered the causative factor of low-grade vascular inflammation in atherosclerosis [6,7]. Reports suggest that plasma CRP levels may be useful for guiding lipid-lowering therapy in individuals who appear to be at low risk for cardiovascular disease according to the traditional Framingham Risk Score [8]. Venugopal and colleagues reported that cytokine stimulation of endothelial cells could result in a much higher local CRP concentration than that observed in plasma and that this higher concentration may contribute to inflammatory and atherogenic effects [10]
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